Continuing Education Activity

In 1943, as the planet was engulfed in WWII and the United States was officially announcing the end of The Great Depression, the most common modern antihistamine, diphenhydramine, was first synthesized. Shortly after, in 1947, orphenadrine was synthesized and used for the treatment of Parkinson disease. With the turn of the decade, antihistamine use became more prevalent, and pediatric deaths increased. A comparison to atropine poisoning and the similar pharmacologic properties between atropine and antihistamines was soon realized. The specific concern of antihistamine toxicity is not due to their competitive H1-receptor binding and sedation but due to their anticholinergic effect. Toxic exposure causes varying degrees of symptoms with differing implications. This activity describes antihistamine toxicity and highlights the role of the interprofessional team in its management.

Objectives:

• Describe the pathophysiology of antihistamine toxicity.
• Outline the presentation of a patient with antihistamine toxicity.
• Review the management options available for antihistamine toxicity.
• Summarize interprofessional team strategies for improving care coordination and outcomes in patients with antihistamine toxicity.

Introduction

In 1943, as the planet was engulfed in WWII and the United States was officially announcing the end of The Great Depression, the most common modern antihistamine, diphenhydramine, was first synthesized. Shortly after, in 1947, orphenadrine was synthesized and used for the treatment of Parkinson disease. As the 1950s started, antihistamine use became more prevalent, and pediatric deaths increased. A comparison to atropine poisoning and their similar pharmacologic properties were soon realized. The specific concern of antihistamine toxicity is not a result of their competitive H1-receptor binding and sedation but due to their anticholinergic effect. Toxic exposure causes varying degrees of symptoms with differing implications. Treatment for antihistamine exposure can range from close monitoring and supportive therapy to rapid pharmacologic intervention.[1][2]

Etiology

Antihistamine toxicity occurs almost exclusively via oral ingestion. Other forms can include intravenous (IV), intramuscular, and topical, but these forms are rare in households.[3]

Epidemiology

The risk for antihistamine toxicity results from ingestion of unintentional toxic doses or attempted suicide mostly occurs in two categories: pediatric patients or older patients. In the former group, antihistamines can be commonly excessively administrated due to their therapeutic sedative properties and worldwide availability. The elderly are more susceptible to their anticholinergic and sedative properties.[4][5]

Pathophysiology

The pathophysiology of antihistamine toxicity varies as the drug has a wide range of therapeutic and toxic effects. Most commonly, ingestion of H1 antihistamines (such as diphenhydramine) manifests with hallucinations or antimuscarinic effects. Rapid IV administration of antihistaminic medications often results in a hallucinogenic effect. A commonly known mnemonic can help one remember the findings of anticholinergic toxicity: "red as a beet, dry as a bone, hot as a hare, blind as a bat, mad as a hatter, and full as a flask." Respectively, this presents with vasodilation and reddening of the skin, anhidrosis and lack of sweat production, hyperthermia due to decreased sweat production, mydriasis causing blurred vision, hallucination, delirium, and urinary retention due to reduced detrusor contraction. Furthermore, diphenhydramine has been shown to potentiate opioid receptors, modulate serotonin function, and enhance dopamine concentration.[6]

Toxicokinetics

Oral ingestion of antihistamines is the primary cause of toxicity. Anticholinergic drugs act by competitively inhibiting the binding of acetylcholine to muscarinic receptors, hence the term antimuscarinic. Within two hours of ingestion, the peak serum concentration is reached, and the maximum antihistaminic effect occurs several hours later. Outside of ingestion, there are some rare incidences of topical exposure causing anticholinergic toxicity. With the peak therapeutic concentration being 0.06 mg/L, many patients with anticholinergic symptoms will have concentrations above the therapeutic levels. Antihistamines, in general, are highly lipid-soluble, with approximately 98% binding to a protein and their volume of distribution ranging from 0.5-30 L/kg. The metabolism of antihistamines is mainly via the hepatic route, except for fexofenadine, levocetirizine, and cetirizine, which are renally excreted and eliminated.

History and Physical

The patient history will often be obtained from parents or supervising adults as patients may be obtunded or too young to communicate. Important history findings would include co-administration of other anticholinergic medications, such as tricyclic antidepressants, atropine, and scopolamine, as the unintentional mixture of medications may increase antimuscarinic toxicity.

Physical exam findings will be divided by organ systems. Neurological symptoms, especially with first-generation H1 antihistaminics, can be found two hours post-ingestion and can manifest as drowsiness, hallucinations, and in pediatric populations, may present as ataxia and irritability. At any point following ingestion, seizures may occur, but they typically occur within the first one to two hours. Visual disturbances may manifest as mydriasis, blurred vision, and diplopia. Cardiovascular findings include tachycardia and both hypertension and hypotension. The binding of sodium and calcium channels may prolong QRS complexes and QT intervals, respectively, as well as the appearance of a Brugada-like syndrome. Lastly, with agitation, irritability, and seizures, some reports of rhabdomyolysis have been documented.

Evaluation

Initially, ECG, temperature, heart rate, respiratory rate, and blood pressure should be assessed. Further diagnostic testing can be useful, although unreliable in some aspects of antihistaminic toxicity. Many common over-the-counter antihistamines produce false negatives for amphetamines. Methadone and phencyclidine in urinary drug screens may lead practitioners down the wrong diagnostic pathways. Extensive testing such as gas chromatography/mass spectroscopy (GC/MS) or liquid chromatography/mass spectroscopy (LC/MS) can be reliable in determining antihistamine concentrations but are not commonly ordered due to the long diagnostic time. Creatinine and blood urea nitrogen (BUN) should be assessed to evaluate kidney function, as well as beta-hCG or other serum pregnancy tests. 

If patients are experiencing seizures or demonstrate extreme agitation, laboratory testing for creatinine kinase should be routinely obtained. IV benzodiazepines should be administrated immediately and with repeated dosing, as needed. If hyperthermic, close monitoring and possible cooling efforts via evaporative methods are indicated. If hypotension occurs, treatment with isotonic fluids should be a sufficient measure, and these should also be administered in the context of rhabdomyolysis. With the findings of worsening QRS complexes or QT intervals, antiarrhythmic medications are indicated to prevent fatal arrhythmias. Administration of 50 mEq of sodium bicarbonate, 2 mg of epinephrine, and IV glucose should be attempted. 

Lastly, if anticholinergic symptoms become severe, physostigmine is indicated. This medication is not currently available, so some authorities recommend the use of oral rivastigmine or intravenous pyridostigmine. These are not FDA-approved for this indication. These medications function by inhibiting cholinesterase, which degrades acetylcholine within the postsynaptic cleft. Contraindications for physostigmine include widened QRS, asthma, other pulmonary diseases, and bradycardia.[7][8]

Treatment / Management

Proper guidelines exist to guide out-of-hospital management. For diphenhydramine and dimenhydrinate, any ingestion under 7.5 mg/kg in children under the age of 6 and less than 300 mg or 7.5 mg/kg for adults and older children, at-home observation is appropriate. If these prove inadequate, prompt evaluation to the closest emergency department is needed. Initially, management should include constant cardiac monitoring and initiation of IV access. Activated charcoal (AC) administration may be indicated, especially if the patient presents shortly after the substance's ingestion. It may be tempting to initiate attempts to increase renal elimination, but due to antihistaminic extensive protein binding and a large volume of distribution, these attempts will be in vain.[9][10][2]

Differential Diagnosis

Differential diagnoses should include:

• Tricyclic antidepressant overdose
• Acetaminophen overdose, hypoglycemia
• Serotonin syndrome

Prognosis

Depending on the amount ingested, the prognosis can vary greatly, but typically with rapid emergency department admission and close cardiac monitoring, the prognosis of toxic antihistaminic ingestion is very good. 

Complications

• Arrhythmias
• Respiratory failure
• Coma
• Rhabdomyolysis
• Hyperthermia
• Seizures

Consultations

• The regional poison control center
• Intensivist
• Nephrologist for dialysis
• Neurologist for any neurological deficits
• Psychiatrist if the poisoning was intentional

Deterrence and Patient Education

Patients need to understand that even though these drugs are available over-the-counter, they can still cause significant toxicity and adverse effects. The healthcare team should counsel regarding the signs of antihistamine overdose. The patient should be told to store these medications in a secure location in the home, away from children. Additionally, these agents should never be combined with sedatives or hypnotics. At discharge, the nurse should educate the patient on ensuring that all medications are stored in child-proof containers. A psychiatrist should see any patient who intentionally consumed the medications prior to discharge. 

Pearls and Other Issues

• Remember: "Red as a beet, dry as a bone, hot as a hare, blind as a bat, mad as a hatter, and full as a flask."
• Brugada-like ECG patterns are seen with anticholinergic toxicity.
• Antihistaminic effects peak after two hours of ingestion.
• Severe sedation could be an initial sign/symptom.
• Many common over-the-counter antihistamines produce false negatives for amphetamines, methadone, and phencyclidine in urinary drug screens.

Enhancing Healthcare Team Outcomes

Antihistamines are commonly found in many over-the-counter medications. Because there is no prescription required, consuming excess amounts is not uncommon. The key to preventing antihistamine toxicity is educating the public. This education and prescribing of antihistamine regimens require the effort of an interprofessional healthcare team. Clinicians need to exercise caution when making a recommendation or prescribing antihistamines. Nursing staff can counsel the patient and ensure they understand dosing and administration. The pharmacist is in an ideal position to educate the public about the potential dangers of these drugs, as well as verify dosing and check for any potential interactions. Those who had developed rhabdomyolysis will need a referral to a physical therapist and enter an exercise program to regain muscle function.[11][12][13] This interprofessional approach will optimize therapeutic results while limiting the potential for toxicity. [Level 5] 

Outcomes

The outcomes of patients with antihistamine toxicity depend on many factors, such as underlying medical conditions, the amount of drug ingested, and any coingestants. The majority of patients do recover fully and are discharged. However, the elderly and children can suffer multiorgan failure from a high dose. First-generation antihistamines like diphenhydramine are more sedating than most other antihistamines. Also, there are reports that this agent is known to cause arrhythmias and seizures.[1] [Level 5]